Significant Growth Inhibition Research Articles

The Growth Inhibition Effect of Different Extracts of Taraxacum Peregrinum Leaves on Breast Cancer Cell Line MDA-MB-468

Background and Objectives: The dandelion plant (Taraxacum officinale) is one of the plants with beneficial effects. In this study, we evaluated the growth inhibition of different extracts of Iranian dandelion (Taraxacum peregrinum) on breast cancer cells. Methods: Ethanolic, methanolic, hydroalcoholic, and aqueous extracts and juice of dandelion leaves were first prepared by the Maceration method. Seven concentrations (0.01, 0.1, 1, 10, 100, 1000, and 10000 mg/mL) were prepared from different extracts. Cisplatin was used as a standard anticancer drug. Their half-maximal inhibitory concentration (IC50) values were evaluated by the MTT assay. Data analysis was done in Excel and GraphPad Prism 8.0.2 software. Results: By increasing the concentration of different extracts, the growth inhibitory effect on cancerous cells increased after 72 hours of exposure. The greatest growth inhibition effect was shown by ethanolic extract (IC50=0.75±0.31 mg/mL) after 72 hours of exposure followed by methanolic extract (IC50=6.25±0.76 mg/mL) and aqueous extract (IC50=6.59±0.94 mg/mL). Their effects were much more significant and better than Cisplatin (IC50=42.57±1.73 mg/mL). However, hydroalcoholic extract and juice of dandelion leaf did not show a significant growth inhibition effect. Conclusion: Given the significant effects of ethanolic, methanolic, and aqueous extracts of Taraxacum peregrinum leaves on inhibiting the growth of the MDA-MB-468 breast cancer cell line, this plant can be used as an herbal supplement for the treatment of breast cancer.

Bacterial Allies in Agricultural Defense: Evaluating Xenorhabdus and Photorhabdus Supernatants Against Phytophthora infestans and Monilinia laxa

Fungal plant pathogens represent a significant threat to global agriculture, affecting crop productivity and food security. Phytophthora infestans and Monilinia laxa are two such pathogens causing blights and brown rot, respectively, in economically vital crops like potato and stone fruits. Developing sustainable management strategies is crucial to mitigate these threats. Xenorhabdus and Photorhabdus bacteria produce various secondary metabolites with different biological activities. This study investigates the antifungal activity of cell-free supernatants from Xenorhabdus and Photorhabdus bacteria against P. infestans and M. laxa. Results demonstrate varying degrees of antifungal efficacy among bacterial species, with X. cabanillasii and X. szentirmaii exhibiting significant suppression of fungal growth. The findings underscore the importance of exploring biocontrol agents in integrated pest management practices.

Mitigating the skin phototoxicity of sonodynamic therapy via singlet oxygen-consuming metal-organic frameworks

Sonodynamic anti-cancer therapy relies on the highly active singlet oxygen to induce potent cell death. However, the non-specific biodistribution of sonosensitizers post systemic administration results in a significant accumulation in the skin, and hence the daylight-induced phototoxicity. Here, we report a smart metal-organic framework-based nanocarrier with titanium dioxide (TiO2) as the sonosensitizer for reduced phototoxicity in the skin. The organic ligand bears the imidazole moiety that can facilely consume singlet oxygen in the skin without compromising the anti-cancer efficacy. The reaction between imidazole moiety and singlet oxygen was confirmed by the density functional theory (DFT). Upon light irradiation, the nanocarrier can significantly reduce the phototoxicity post light irradiation in a range of normal cells in vitro and in a mouse model in vivo. Meanwhile, the ligand contains a disulfide moiety that can deplete glutathione and orchestrate the singlet oxygen-induced toxicity in the CT-26 colon cancer cells. As a result, the nanocarrier showed superior in vivo antitumor efficacy in a CT-26 tumor-bearing mice model, leading to significant suppression of tumor growth and improved animal survival rates. The current work provides a tailored nanoscale particle engineering approach to simultaneously minimize phototoxicity in the skin and sensitize sonodynamic anti-cancer therapy.

A Novel Lipid Nanoparticle NBF-006 Encapsulating Glutathione S-Transferase P siRNA for the Treatment of KRAS-driven Non-small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancers, and KRAS mutations occur in 25-30% of NSCLC. Our approach to developing a therapeutic with the potential to target KRAS mutant NSCLC was to identify a new target involved in modulating signaling proteins in the RAS pathway. Glutathione S-Transferase P (GSTP) known as a Phase II detoxification enzyme has more recently been identified as a modulator of MAP kinase-related cell-signaling pathways. Therefore, developing a GSTP siRNA may be an effective therapeutic approach to treat KRAS mutant NSCLC. The lead drug product candidate (NBF-006) is a proprietary siRNA-based lipid nanoparticle (LNP) comprising GSTP siRNA (NDT-05-1040). Here, studies using a panel of KRAS mutant NSCLC cell lines demonstrated that NDT-05-1040 is a very potent and selective GSTP siRNA inhibitor. Our Western blot analysis showed that NDT-05-1040 effectively decreased the phosphorylation of MAPK and PI3K pathway components while upregulating apoptotic signaling cascade. Our in vivo studies revealed statistically significant higher distribution of NBF-006 to the lungs and tumor as compared to liver. In the subcutaneous and orthotopic tumor models, NBF-006 led to a statistically significant and dose dependent anti-tumor growth inhibition. Further, quantitative image analysis of PCNA and PARP staining showed that NBF-006 decreased proliferation and induced apoptosis, respectively, in tumors. Additionally, in a surgically implanted orthotopic lung tumor model, the survival rate of the NBF-006 treatment group was significantly prolonged (P <0.005) as compared to the vehicle control group. Together, these preclinical studies supported advancement of NBF-006 into clinical studies.

Medical-grade honey has superior antibacterial properties against common bacterial isolates in wound cultures of dogs and cats in comparison to non-medical-grade honey types.

To compare the antibacterial activities of different types of honey against common bacterial isolates cultured from wounds of dogs and cats. 4 types of honey were used including a medical-grade manuka honey, a non-medical-grade manuka honey, a locally sourced non-medical-grade honey (non-MGH), and a commercially sourced non-MGH. Bacterial isolates were obtained from clinical wound cultures of dogs and cats including Staphylococcus pseudintermedius, Escherichia coli, Enterococcus faecalis, and Pseudomonas aeruginosa. The macro-broth dilution method was used to analyze the MIC and minimum bactericidal concentration. The percentage of growth inhibition was assessed for different types of honey at different concentrations using a generalized linear regression model. Medical-grade honey exhibited the lowest minimum bactericidal concentration against S pseudintermedius, E faecalis, and P aeruginosa, alongside the lowest MIC at 90% with statistically significant higher bacterial growth inhibition in medium and low concentrations. Non-medical-grade manuka honey had a similar bactericidal activity against S pseudintermedius and P aeruginosa compared to locally and commercially sourced non-MGH. In this in vitro study, MGH exhibited superior antibacterial activity against all bacterial isolates compared to other types of honey. Medical-grade honey displayed the greatest antibacterial activity against common wound pathogens and could be considered over other types of honey for wound management in cats and dogs. Locally and commercially sourced non-MGH appears to have a comparative efficacy against certain bacteria compared to non-medical-grade manuka honey and is more cost effective. Further in vivo studies are needed to confirm these findings.

Targeting KRAS-mutant pancreatic cancer through simultaneous inhibition of KRAS, MEK, and JAK2.

The Kirsten rat sarcoma (KRAS) oncogene was considered "undruggable" until the development of sotorasib, a KRASG12C selective inhibitor that shows favorable effects against lung cancers. MRTX1133, a novel KRASG12D inhibitor, has shown promising results in basic research, although its effects against pancreatic cancer are limited when used alone. Therefore, there is an urgent need to identify effective drugs that can be used in combination with KRAS inhibitors. In this study, we found that administration of the KRAS inhibitors sotorasib or MRTX1133 upregulated STAT3 phosphorylation and reactivated ERK through a feedback reaction. The addition of the MEK inhibitor trametinib and the JAK2 inhibitor fedratinib successfully reversed this effect and resulted in significant growth inhibition in vitro and in vivo. Analyses of sotorasib- and MRTX1133-resistant cells showed that trametinib plus fedratinib reversed the resistance to sotorasib or MRTX1133. These findings suggest that the JAK2-mediated pathway and reactivation of the MAPK pathway may play key roles in resistance to KRAS inhibitors in pancreatic cancers. Accordingly, simultaneous inhibition of KRAS, MEK, and JAK2 could be an innovative therapeutic strategy against KRAS-mutant pancreatic cancer.

Targeted nanoliposomes of oncogenic protein degraders: Significant inhibition of tumor in lung-cancer bearing mice

With 60 % of non-small cell lung cancer (NSCLC) expressing epidermal growth factor receptor (EGFR), it has been explored as an important therapeutic target for lung tumors. However, even the well-established EGFR inhibitors tend to promptly develop resistance over time. Moreover, strategies that could impede resistance development and be advantageous for both EGFR-Tyrosine kinase inhibitor (TKI)-sensitive and mutant NSCLC patients are constrained. Based on the critical relationship between EGFR, c-MYC, and Kirsten rat sarcoma virus (K-Ras), simultaneous degradation of EGFR and Bromodomain-containing protein 4 (BRD4) using “Proteolysis Targeting Chimeras (PROTACs)” could be a promising approach. PROTACs are emerging class of oncoprotein degraders but very challanging to deliver in vivo. Compared to individual IC50s, strong synergism was observed at 1:1 ratio of BPRO and EPRO in NSCLC cell lines with diverse mutation. Significant inhibition of cell growth with higher cellular apoptosis was observed in 2D and 3D-based cell assays in nanomolar concentrations. EGFR activation assay revealed 47.60 % EGFR non-expressing cells confirming EGFR-degrading potential of EPRO. A lung cancer specific nanoliposomal formulation of EGFR and BRD4-degrading PROTACs (EPRO and BPRO) was prepared and characetrized. Successful encapsulation of the two highly lipophilic molecules was achieved in EGFR-targeting nanoliposomal carriers (T-BEPRO) using a modified hydration technique. T-BEPRO revealed a particle size of 109.22 ± 0.266 nm with enhanced cellular uptake and activity. Remarkably, parenterally delivered T-BEPRO in tumor-bearing mice showed a substantially higher % tumor growth inhibition (TGI) of 77.6 % with long-lasting tumor inhibitory potential as opposed to individual drugs.

Simplified Lipid Nanoparticles for Tissue- And Cell-Targeted mRNA Delivery Facilitate Precision Tumor Therapy in a Lung Metastasis Mouse Model.

mRNA-based applications have achieved remarkable success in the development of next-generation vaccines and the treatment of diverse liver diseases. Overcoming the challenge of delivering mRNA to extrahepatic tissues, especially specific cells within tissues, is crucial for precision therapy. In this study, a platform is developed for selective mRNA delivery to desired cells within tissues by combining lipid nanoparticle (LNP)-based targeted delivery with mRNA sequence-controlled expression. Through systematic optimization, a three-component LNP platform is developed, enabling targeted mRNA delivery to the lung, liver, and spleen. The incorporation of unique microRNA target sites into the mRNA scaffold further enhances control over protein translation in specific cells within the target tissue. This combined strategy, named SELECT (Simplified LNP with Engineered mRNA for Cell-type Targeting), demonstrates its efficacy in distinguishing mRNA expression between tumor and normal cells based on intracellular microRNA abundance. SELECT encapsulating mRNA encoding a tumor-specific cytotoxic protein, human ELANE, exhibits selective mRNA delivery to tumor lesions and significant inhibition of tumor growth in a mouse model of melanoma lung metastasis. Overall, SELECT has great potential as a new precision tumor treatment approach and also offers promising prospects for other mRNA therapies targeting specific cell types.

Enhanced Oncolytic Potential of Engineered Newcastle Disease Virus Lasota Strain through Modification of Its F Protein Cleavage Site.

Newcastle disease virus (NDV) is an oncolytic virus whose F protein cleavage activity is associated with viral infectivity. To explore the potential of modifying F protein cleavage activity to enhance antitumor effects, we constructed a recombinant NDV LaSota strain by replacing its F protein cleavage site with that from the mesogenic Beaudette C (BC) strain using reverse genetics techniques. The resulting virus, rLaSota-BC-RFP, demonstrated significantly enhanced infectivity and tumor cell suppression on the murine melanoma B16F10 cell, characterized by higher cytotoxicity and increased apoptosis compared to its parental strain, rLaSota-RFP. In vivo, rLaSota-BC-RFP treatment of B16F10 tumors in C57BL/6 mice resulted in significant tumor growth inhibition, improved survival rate, and induction of tumor-specific apoptosis and necrosis. Additionally, the rLaSota-BC-RFP treatment enhanced immunostimulatory effects within the tumor microenvironment (TME), characterized by increased infiltration of CD4+ and CD8+ T cells and elevated levels of antitumor immune modulator cytokines, including mouse IL-12, IFN-γ, IL-15, and TNF-α, in the rLaSota-BC-RFP-treated tumor tissues. Collectively, these findings demonstrate that the mesogenic F protein cleavage site enhances the oncolytic potential of the NDV LaSota strain, suggesting that rLaSota-BC-RFP is a promising oncolytic viral vector for gene delivery in cancer immunotherapy.

Nerol as a Novel Antifungal Agent: In Vitro Inhibitory Effects on Fusarium oxysporum, Pestalotiopsis neglecta, and Valsa mali and Its Potential Mechanisms against F. oxysporum.

This study explores the in vitro antifungal effects of nerol, a linear acyclic monoterpene alcohol of plant origin, on Fusarium oxysporum, Pestalotiopsis neglecta, and Valsa mali. To further investigate the antifungal mechanism of nerol against F. oxysporum, we examined changes in mycelial morphology and cell membrane integrity-related indices, as well as the activities of antioxidant and pathogenicity-related enzymes. The results demonstrated that nerol exhibited significant concentration-dependent inhibition of mycelial growth in all three fungi, with EC50 values of 0.46 μL/mL for F. oxysporum, 1.81 μL/mL for P. neglecta, and 1.26 μL/mL for V. mali, with the strongest antifungal activity observed against F. oxysporum. Scanning electron microscopy revealed that nerol severely disrupted the mycelial structure of F. oxysporum, causing deformation, swelling, and even rupture. Treatment with 0.04 μL/mL nerol led to significant leakage of soluble proteins and intracellular ions in F. oxysporum, and the Na+/K+-ATPase activity was reduced to 28.02% of the control, indicating enhanced membrane permeability. The elevated levels of hydrogen peroxide and malondialdehyde, along with propidium iodide staining of treated microconidia, further confirmed cell membrane disruption caused by nerol. Additionally, after 12 h of exposure to 0.04 μL/mL nerol, the activity of superoxide dismutase in F. oxysporum decreased to 55.81% of the control, and the activities of catalase and peroxidase were also significantly inhibited. Nerol markedly reduced the activities of pathogenicity-related enzymes, such as endo-1,4-β-D-glucanase, polygalacturonase, and pectin lyase, affecting fungal growth and virulence. In conclusion, nerol disrupts the cell membrane integrity and permeability of F. oxysporum, reduces its virulence, and ultimately inhibits fungal growth, highlighting its potential as an alternative to chemical fungicides for controlling F. oxysporum.

SLC45A4 is involved in malignant progression of ovarian cancer through glycolytic metabolic reprogramming

Tumor cells promote malignant behaviors such as proliferation, invasion, and metastasis of cancer cells through glucose metabolic reprogramming, but the role of the H-dependent sugar cotransporter SLC45A4 in regulating metabolic reprogramming in ovarian cancer (OC) remains largely unknown. This study aimed to investigate the effects of SLC45A4 silencing on the transcriptome spectrum of ovarian cancer cells (OCC), glucose uptake, lactic acid production, intracellular ATP levels, and the expression and activity of HIF-α glycolysis signaling pathway. The results showed that SLC45A4 is overexpressed in OC and its elevated expression correlates with adverse clinical outcomes in OC patients. Silencing of SLC45A4 significantly inhibited the proliferation, invasion, and metastasis of OCC by suppressing glucose uptake and glycolysis, and it also reduced the expression of HIF-α glycolysis signaling pathway in OC tissues. In vivo experiments using shRNA to knock down SLC45A4 in xenograft models in nude mice demonstrated a significant inhibition of tumor growth. These findings suggest that SLC45A4 silencing can restrain the malignant progression of OC by inhibiting glucose uptake in OCC and affecting the reprogramming of glycolytic energy metabolism, indicating that SLC45A4 may serve as a potential therapeutic target for OC intervention.

Discovery of Promising Sulfadiazine Derivatives With Anti‐Proliferative Activity Against Tumor Cell Lines

ABSTRACTA novel series of pyrimidine sulfonamide derivatives was synthesized through a strategic approach involving the creation of substituted dihydropyrimidinyl‐benzenesulfonamides and subsequent transformation into their chlorinated analogues. These compounds were then subjected to reactions with various amines and phenols, yielding unique substituted sulfapyrimidines. These novel structures integrated essential pharmacophores such as phenols, secondary amines, and benzenesulfonamide moieties, each contributing distinct biological potencies, chemical reactivity, and enhanced pharmacological features. In the pursuit of effective anticancer agents, the newly substituted pyrimidine sulfonamides were characterized using spectroscopic and x‐ray diffraction techniques. The compounds were evaluated for their anti‐proliferative potency against the NCI 60‐cell lines panel, revealing that compound 7c exhibited significant growth inhibition across multiple cancer cell lines. Further assessment through MTT assay on HCT‐116 and MCF‐7 cell lines demonstrated cytotoxicity, while cell cycle analysis of MCF‐7 cells treated with compound 7c revealed arrest at the S phase. Moreover, the effect of 7c on programmed cell death was evaluated using the Annexin V/PI apoptosis assay. The observed promising activity positions these pyrimidine‐based scaffolds as potential candidates for future drug development, offering valuable insights for medicinal chemists engaged in the design and synthesis of anticancer drugs.

Antimicrobial effects of a multimodal wound matrix against methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa in an in vitro and an in vivo porcine wound model.

Chronic non-healing wounds pose significant challenges due to an elevated inflammatory response caused in part by bacterial contamination (Physiol Rev. 2019;99:665). These wounds lead to billions being spent in the health care system worldwide (N Engl J Med. 2017;376:2367, Int J Pharm. 2014;463:119). We studied the in-vitro and in-vivo antimicrobial effects of a multimodal wound matrix (MWM) against two common wound pathogens, Methicillin-Resistant Staphylococcus aureus (MRSA USA300) and Pseudomonas aeruginosa ATCC 27312 (PA27312) (Int Wound J. 2019;16:634). The in-vitro study conducted was a zone of inhibition test with the two microbes at 104 Log CFU/mL inoculated on Tryptic soy agar with 5% sheep blood (TSAII) plates. Treatments used were MWM, Mupirocin (Positive control for MRSA), Silver Sulfadiazine (Positive Control for PA), Petrolatum and Sterile Saline (both serving as Negative Controls). Treatments were allowed to diffuse into the agar for 3 h and then were incubated for 24 h at 37°C. The in-vivo study utilized a deep dermal porcine wound model (22 × 22 × 3 mm) created on six animals. Three animals were inoculated with MRSA USA300 and the other three with PA27312 with each allowing a 72-h biofilm formation. After 72 h, baseline wounds were assessed for bacterial concentration and all remaining wounds were treated with either MWM alone, Silver Treatment or Untreated Control. Wounds were assessed on days 4, 8 and 12 after treatment application for microbiological analysis. In-vitro, MWM exhibited significant inhibition of MRSA USA300 and PA27312 growth when compared to negative controls (p ≤ 0.05). Likewise, in-vivo, the MWM-treated wounds exhibited a significant (p ≤ 0.05) bacterial reduction compared to all other treatment groups, especially on days 8 and 12 for both pathogens. MWM demonstrated promise in addressing colonized wounds with biofilms. Additional studies on MWM's benefits and comparisons with existing treatments are warranted to optimize wound care strategies (Adv Wound Care. 2021;10:281).

Assembly of 2′,3′-Cyclic guanosine Monophosphate-Adenosine monophosphate and their spontaneous intracellular disassembly for enhanced antitumor immunity via natural STING pathway activation

The stimulator of interferon genes (STING) pathway plays an important role in remodeling the immunosuppressive tumor microenvironment (TME). Cyclic dinucleotides (CDNs), the natural ligands of STING, activate innate immunity to enhance tumor immunogenicity. However, the anionic properties of CDNs result in poor membrane permeability, while their rapid metabolism by enzymes hinders the efficient targeting and activation of STING in vitro and in vivo. To improve the bioavailability and antitumor immunity of CDNs, we designed a hydrogen-bonding-based supramolecular approach for 2′,3′-cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP). Leveraging the synthetic molecules cytosine-uracil-hexane (CUH), we formulated supramolecular micelles of cGAMP via specific hydrogen bonds in aqueous solutions. Micelles comprising the CUH-cGAMP complex enhanced the biological efficacy of cGAMP by increasing its stability, thereby prolonging the activation of STING-mediated innate and adaptive immunity. We demonstrated that CUH-cGAMP stands as a promising candidate for immunotherapy, exhibiting significant inhibition of tumor growth in a CT26 syngeneic mouse model.

Characterization of exopolysaccharide/potato starch nanocomposite films loading g-C3N4 and Ag and their potential applications in food packaging

The interest in nanocomposite films incorporating edible ingredients and active nanoparticles has surged due to their potential to enhance food quality and prolong shelf-life. This research focused on developing innovative exopolysaccharides (EPS)/potato starch (PS) nanocomposite films integrated with g-C3N4 and AgNO3. Extensive analysis was conducted to assess the microstructure, physical attributes and antimicrobial properties of these films. Fourier transform infrared (FT-IR) analysis revealed electrostatic and hydrogen bonding interactions within the film components. X-ray diffraction (XRD) and X-ray photoelectron spectrometer (XPS) data indicated a high level of compatibility among EPS, PS, g-C3N4, and AgNO3, with no new absorption peaks or characteristic signals of C3N4 and Ag appearing in the nanocomposite films patterns. The thickness, water solubility and water vapor permeability (WVP) of the EPS-PS-C3N4-Ag nanocomposite film increased due to the addition of g-C3N4, reached 0.31 ± 0.03 nm, 36.61 ± 1.76 % and 1.42 ± 0.34 × 10−10 g−1 s−1 Pa−1, respectively. While transparency, swelling degree, and oxygen permeability (OP) significantly decreased, reached 26.18 ± 2.38 %, 63.01 ± 2.51 % and 41.98 ± 1.28 %, respectively. Scanning electron microscopy (SEM) and atomic force microscope (AFM) images depicted an augmented roughness and porosity on the film surface upon integration of g-C3N4 and AgNO3. Moreover, the EPS-PS-C3N4-Ag nanocomposite film displayed enhanced mechanical strength due to the presence of g-C3N4. The melting temperature (Tm) of EPS-PS-C3N4-Ag nanocomposite film was 313.3 °C, the removal rates of DPPH and ABTS was 66.11 ± 2.87 % and 45.09 ± 1.23 % respectively. Significant inhibition of microbial growth was observed in film containing g-C3N4 and AgNO3, which demonstrated no toxicity towards NIH-33 cells, suggesting their potential application as promising active packaging material for food preservation.

Physicochemical, structural, and biological properties of novel water-soluble polysaccharide derived from the Tunisian Hammada scoparia plant and its application on beef meat preservation

This work aims to characterize a novel water-soluble polysaccharide from Hammada scoparia leaves named PSP. The Infrared (FT-IR) and nuclear magnetic resonance (NMR) spectra confirmed the presence of different polysaccharide functional bands. The High-Performance Liquid Chromatography (HPLC) analysis identified a heteropolysaccharide composed of two monosaccharides. A semi-crystalline structure of PSP was proved using the X-ray diffraction (XRD) and Scanning Electron Microscopy (SEM) analysis. The evaluation of the antioxidant activity revealed an interesting potential to prevent oxidative stress.Additionally, PSP showed interesting functional propreties such as good oil and water retention abilities, higher foaming stability, and higher emulsifying capacity and stability. However, the effect of PSP on the oxidation of lipids in the ground beef meat was established during nine days at 4 °C. Obtained data revealed a significant decrease in malondialdehyde levels, inhibition of metmyoglobin (MetMb) accumulation, and significant inhibition of microbial growth compared with the control sample during storage. Moreover, incorporating PSP in minced meat proved color pH and moisture stability. Overall, the findings in the present study confirmed that PSP could be considered a natural bioactive polymer for food applications.

Optimized lipid nanoparticles enable effective CRISPR/Cas9-mediated gene editing in dendritic cells for enhanced immunotherapy

Immunotherapy has emerged as a revolutionary approach to treat immune-related diseases. Dendritic cells (DCs) play a pivotal role in orchestrating immune responses, making them an attractive target for immunotherapeutic interventions. Modulation of gene expression in DCs using genome editing techniques, such as the CRISPR-Cas system, is important for regulating DC functions. However, the precise delivery of CRISPR-based therapies to DCs has posed a significant challenge. While lipid nanoparticles (LNPs) have been extensively studied for gene editing in tumor cells, their potential application in DCs has remained relatively unexplored. This study investigates the important role of cholesterol in regulating the efficiency of BAMEA-O16B lipid-assisted nanoparticles (BLANs) as carriers of CRISPR/Cas9 for gene editing in DCs. Remarkably, BLANs with low cholesterol density exhibit exceptional mRNA uptake, improved endosomal escape, and efficient single-guide RNA release capabilities. Administration of BLANmCas9/gPD-L1 results in substantial PD-L1 gene knockout in conventional dendritic cells (cDCs), accompanied by heightened cDC1 activation, T cell stimulation, and significant suppression of tumor growth. The study underscores the pivotal role of cholesterol density within LNPs, revealing potent influence on gene editing efficacy within DCs. This strategy holds immense promise for the field of cancer immunotherapy, offering a novel avenue for treating immune-related diseases.

Design, synthesis and pharmacological evaluation of 1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine derivatives as p21-activated kinase 4 inhibitors for treatment of pancreatic cancer

The p21-activated kinase 4 (PAK4), a key regulator of malignancy, is negatively correlated with immune infiltration and has become an emergent drug target of cancer therapy. Given the lack of high efficacy PAK4 inhibitors, we herein reported the identification of a novel inhibitor 13 bearing a tetrahydrobenzofuro[2,3-c]pyridine tricyclic core and possessing high potency against MIA PaCa-2 and Pan02 cell lines with IC50 values of 0.38 and 0.50 μmol/L, respectively. This compound directly binds to PAK4 in a non-ATP competitive manner. In the mouse Pan02 model, compound 13 exhibited significant tumor growth inhibition at a dose of 100 mg/kg, accompanied by reduced levels of PAK4 and its phosphorylation together with immune infiltration in mice tumor tissue. Overall, compound 13 is a novel allosteric PAK4 inhibitor with a unique tricyclic structural feature and high potency both in vitro and in vivo, thus making it worthy of further exploration.

Mesoporous polydopamine (MPDA)-based drug delivery system for oral chemo-photothermal combinational therapy of orthotopic colon cancer

Oral nano-drug delivery systems offering combination therapy have garnered significant interest in colon cancer treatment due to their precision in targeting tumors and minimizing peripheral tissue exposure. However, challenges such as the complex gastrointestinal environment and effective retention of nanoparticles in the colon have impeded further advancement. We developed a novel oral drug delivery system designed for localized treatment of colon cancer via chemotherapy and photothermal therapy (PTT). This system utilized mesoporous polydopamine (MPDA) as a photothermal carrier for doxorubicin hydrochloride (DOX), with surface modification using folic acid (FA) to enhance systemic tumor targeting. Additionally, to ensure gastrointestinal retention and precise colon localization, the nanoparticles were coated with an enteric-soluble material, ES100, resulting in the formulation MPDA-FA-DOX/ES100. This formulation exhibited high photothermal conversion efficiency, robust photothermal stability, and responsive drug release under near-infrared (NIR) laser stimulation. FA modification significantly enhanced the cellular uptake of nanoparticles by CT26 cells, promoting greater cytotoxic effects through combined chemotherapy and PTT. In vivo, MPDA-FA-DOX/ES100 demonstrated superior accumulation in colon tumor tissues and substantial photothermal effects, and notably, the CT/PTT group demonstrated significant tumor growth inhibition along with excellent biocompatibility. Collectively, these findings highlight the clinical potential of MPDA-FA-DOX/ES100 as an effective platform for localized and synergistic CT/PTT of colon cancer.

Arabidopsis MORC1 and MED9 Interact to Regulate Defense Gene Expression and Plant Fitness.

Arabidopsis MORC1 (Microrchidia) is required for multiple levels of immunity. We identified 14 MORC1-interacting proteins (MIPs) via yeast two-hybrid screening, eight of which have confirmed or putative nuclear-associated functions. While a few MIP mutants displayed altered bacterial resistance, MIP13 was unusual. The MIP13 mutant was susceptible to Pseudomonas syringae, but when combined with morc1/2, it regained wild-type resistance; notably, morc1/2 is susceptible to the same pathogen. MIP13 encodes MED9, a mediator complex component that interfaces with RNA polymerase II and transcription factors. Expression analysis of defense genes PR1, PR2, and PR5 in response to avirulent P. syringae revealed that morc1/2 med9 expressed these genes in a slow but sustained manner, unlike its lower-order mutants. This expression pattern may explain the restored resistance and suggests that the interplay of MORC1/2 and MED9 might be important in curbing defense responses to maintain fitness. Indeed, repeated challenges with avirulent P. syringae triggered significant growth inhibition in morc1/2 med9, indicating that MED9 and MORC1 may play an important role in balancing defense and growth. Furthermore, the in planta interaction of MED9 and MORC1 occurred 24 h, not 6 h, postinfection, suggesting that the interaction functions late in the defense signaling. Our study reveals a complex interplay between MORC1 and MED9 in maintaining an optimal balance between defense and growth in Arabidopsis.